The invention pertains generally to apparatus and method for therapeutically treating musculoskeletal tissue in vivo. In particular, the invention pertains to the combined use of biophysical and biochemical stimuli for therapeutically treating bone and other musculoskeletal tissue in vivo. More particularly, the invention pertains to the combined use of ultrasound and a bone growth factor for therapeutically treating bone in vivo.
In recent years, various attempts have been made to stimulate bone growth. These approaches have not been particularly successful, and as a consequence have not as yet received broad acceptance by either the professional (i.e., medical) or lay (i.e., patient) community. Further, this lack of effectiveness has resulted in a reluctance of the third-party payer community (e.g., insurance companies and HMO""s) to offer reimbursement, so that commercialization of such stimulation technologies has been stalled.
A number of issued patents disclose methods and apparatuses to biophysically treat bone and other musculoskeletal tissue. For example, Kaufman et al., U.S. Pat. No. 5,309,808 disclose apparatus and method for therapeutically treating and/or quantitatively evaluating bone tissue in vivo, by subjecting bone to an ultrasonic signal pulse of finite duration, and involving a composite sine-wave signal consisting of plural discrete frequencies. These frequencies are spaced in the ultrasonic region to approximately 2 MHz; the excitation signal is repeated substantially in the range 1 to 1000 Hz. In a closely related patent, Kaufman et al., U.S. Pat. No. 5,458,130, the same inventors extend the apparatus and method to the treatment to musculoskeletal tissue in general. In another patent by the same inventors, Kaufman et al., U.S. Pat. No. 5,547,459 disclose apparatus and method for therapeutically treating bone tissue in vivo, by subjecting bone to an ultrasonic sinusoidal signal pulse peculiarly modulated by a sinusoidal signal with a frequency between about 0 Hz and 25 kHz.
Duarte, U.S. Pat. No. 4,530,360 discloses apparatus and a method of using ultrasonic energy for therapeutic treatment of bone tissue in vivo, using a pulsed sine wave at substantially a single frequency within the range 1.3 to 2.0 MHz, and at a pulse repetition rate of 100 to 1000 Hz.
McLeod et al., U.S. Pat. Nos. 5,103,806 and 5,191,880 disclose methods for promotion of growth bone tissue and the prevention of osteopenia, using mechanical loading of the bone tissue. In both patents, the inventors apply a mechanical load to the bone tissue at a relatively low level on the order of between about 50 and about 500 microstrain, peak to peak, and at a relatively high frequency in the range of about 10 and 50 hertz.
Bassett et al., U.S. Pat. No. 4,928,959 disclose method and device for providing active exercise treatment for a patient suffering from a bone disorder. A patient is subjected to an impact load in order to stimulate bone growth, with an impact load sensor being used to monitor the treatment strength.
Numerous other patents disclose methods for stimulating bone growth relying on the generation of electromagnetic signals. For example, Ryaby et al. U.S. Pat. Nos. 4,105,017 and 4,315,503 describe methods for promoting bone healing in delayed and nonunion bone fractures, using an asymmetric pulsed waveform. In U.S. Pat. No. 4,993,413, McLeod et al. disclose method and apparatus for inducing a current and voltage in living tissue to prevent osteoporosis and to enhance new bone formation. They disclose the use of a symmetrical low frequency and low intensity electromagnetic signal substantially in the range of 1-1000 Hertz. In Liboff et al., U.S. Pat. No. 5,318,551 (and others), methods are disclosed which incorporate the combined use of a static and time-varying magnetic field to stimulate bone healing and growth. Specific amplitudes and frequencies are disclosed for optimal enhancement of bone growth, based on the theory of xe2x80x9cion-cyclotron resonance.xe2x80x9d
Non-biophysical methods, i.e., methods which use a biochemical compound (or generically a xe2x80x9cbone growth factorxe2x80x9d) to stimulate bone growth have also been described. For example, Ammann et al., U.S. Pat. No. 5,604,204 disclose method for inducing bone growth using a bone growth factor composition known as TGF-xcex2, in an animal, locally at a bone site where skeletal tissue is deficient. The TGF-xcex2 is contained in a xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d in an amount effective to induce bone growth at the bone site.
Dunstan et al., U.S. Pat. No. 5,656,598 disclose method involving therapeutic (biochemical) compositions for the prevention and treatment of pathological conditions involving bone and dental tissue. The invention achieves its objectives by administering a fibroblast growth factor (FGF-1) to an animal or human in need of such treatment.
Oppermann et al., U.S. Pat. Nos. 5,354,557 and 5,814,604, disclose methods involving osteogenic devices. (The use of the term xe2x80x9cdevicesxe2x80x9d should be understood to denote a biochemical compound or bone growth factor in an appropriate matrix for delivery to the bone.) The osteogenic devices are comprised of a matrix containing substantially pure naturally-sourced mammalian osteogenic protein. They also disclose DNA and amino acid sequences for novel polypeptide chains useful as subunits of dimeric osteogenic proteins, and methods of using the osteogenic devices to mimic the natural course of endochondral bone formation in mammals. The inventors also disclose methods of producing osteogenic proteins using recombinant DNA technology.
Balazs et al., U.S. Pat. No. 5,128,326, disclose systems based on hyaluronans derivatives, as well as methods for preparing same. Such systems are useful for treatment of cartilage tissue.
Falk et al., U.S. Pat. No. 5,792,753 disclose a pharmaceutical composition which contains a drug that inhibits prostaglandin synthesis, and also contains an amount of a form of hyaluronic acid. The composition is topically administered to the skin and is useful for the treatment of cartilage as it relates to arthritis.
Wang et al., U.S. Pat. No. 5,4,877,864, disclose human and bovine bone and cartilage inductive (biochemical) factors. Such factors may be produced by recombinant techniques and may be useful for treatment of various musculoskeletal tissue defects.
The prior art, exemplified by the references that have been briefly discussed, have used either biophysical or biochemical approaches, to promote bone growth, bone ingrowth and bone healing, or other musculoskeletal tissue healing or growth. In either case, that is, in the biophysical approach (including for example, ultrasound methods), or in the biochemical approach (including, for example, bone growth factors such as TFG-xcex2), treatment has not been effective enough to lead to widespread use. However, the present inventors have discovered how to dramatically enhance the efficacy of such therapeutic methods for bone growth and other musculoskeletal tissue healing, taking advantage of the uniquely synergistic nature associated with the two basic approaches.
It is accordingly an object of the invention to provide an improved method and apparatus for therapeutically treating bone and other musculoskeletal tissue in vivo, whereby to promote bone and other musculoskeletal tissue healing, growth and ingrowth.
Another object is to meet the above object, such that bone and musculoskeletal tissue healing, growth and ingrowth may be more efficiently and more effectively treated than heretofore.
A specific object is to take advantage of the synergistic properties associated with combined application of biochemical and biophysical treatment methods whereby to achieve the indicated objectives.
A further specific object is to take advantage of the synergistic properties associated with biochemical and biophysical treatment methods whereby to achieve much shorter total treatment times, shortening both daily treatment times and the total number of daily treatments required.
A further specific object is to achieve the above objects with a specially chosen set of ultrasonic signals, designed with respect to a mathematical model for evaluating the displacement associated with a biochemical compound.
It is a general object to achieve the foregoing objects with apparatus components that are for the most part commercially available.
Briefly stated, the invention in its presently preferred form achieves the foregoing objectives by injecting through skin overlying a bone to be treated, a biochemical compound containing an osteogenic protein (i.e., a bone growth factor). Soon after this injection, the bone is iteratively subjected to an ultrasonic signal of finite duration, consisting of frequency components in the ultrasonic region to approximately 10 MHz, delivered by a transducer placed on skin overlying the bone; the excitation signal is repeated in the range of 1 to 1000 Hz. The exposure time for ultrasonic therapy is chosen to be in the range of 1 minute to 1 hour, for 1 to 3 times a day, for a period of days as necessary for healing or for promoting bone growth or bone ingrowth. In the presently preferred embodiment of the invention, a single ultrasound treatment lasting for 15 minutes is applied within one hour of the injection of the bone growth factor, and achieves the indicated objectives.
In the currently preferred embodiment, the ultrasonic signal is generated by a pulser to which the transducer is connected. The pulser emits a negative going narrow square pulse of about xe2x88x92300 volts; the duration of the pulse itself is about 0.3 microseconds. The transducer emits an ultrasound signal with a center frequency of about 3 MHz, and of about 1 microsecond in duration, thereby creating a broadband exponentially damped 3 MHz sinusoidal signal. The signal is repeated at a repetition rate of 4,500 Hz.
In the presently preferred embodiment, the ultrasound interacts with the bone growth factor in such a way as to enhance in a positive fashion the bone healing, bone growth and bone ingrowth processes. This combined effect of the ultrasound therapy in the presence of the bone growth factor produces a synergistically enhanced response, namely one that is many times more effective than that which would be produced by having either agent acting alone. In this way, the present invention, besides offering much enhanced bone healing, bone growth and bone ingrowth results, also benefits from significantly shorter treatment periods, both from reductions in the total daily treatment time, but even more importantly, from dramatic reductions in the total number of days required for treatment, which result from application of the methods disclosed herein.